Opioid agonists are used therapeutically for the treatment of pain, or during detoxification treatment as a replacement drug. Opioid agonists are substances which have effects similar to opium, but are not chemically related. Opioid agonists exert their effects by stimulating opioid receptors (also called opiate receptor). Three main types of opioid receptors include mu (μ), delta (δ) and kappa (κ). These opioid receptors are widely distributed in the brain and in some peripheral areas. The pharmacological response caused by complex opioid agonist/receptor formations depends on the type of opioid receptor being stimulated.
Commonly used opioid agonists include, but are not limited to, alfentanil, anileridine, apomorphine, buprenorphine, butorphanol, carfentanil, codeine, diamorphine (“heroin”), dextropropoxyphene, dihydromorphine, fentanyl, hydrocodone, hydromorphone, levallorphan, levophenacylmorphan, levorphanol, methadone, morphine, nalbuphine, nalorphine, norievophanoi, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tramadol, etc. In addition, a number of endogenous substances may be classified as opioid agonists such as dynorphins, endorphins, endorphins, enkephalins, nociceptors, etc.
Opioid agonists may have many undesirable side effects including drowsiness, respiratory depression, constipation, nausea, vomiting, etc. Accordingly, the use of opioid agonists should be handled with care, especially in the hospital or any health care setting. In addition, treatment with opioid agonists pose many risks of misuse as opioid agonists may be used as a substitute for hard drugs. As a result, supply clinics require expensive security systems for tracking and controlling such drugs. Finally, as opioid agonists may be highly addictive, increased dosages resulting from long-term treatment may cause the patient to become dependent, especially when the administration of the therapy is “on demand.” Accordingly, an opioid agonist-based therapy requires strict regulation and strong involvement of medical staff, which is problematic in the context of cost optimization.
The administration of opioids predominantly involve injectable solutions, especially in the hospital environment. This form of administration has a number of advantages, for example, the effect is very fast and bioavailability is well controlled. However, administration by injection is has some drawbacks. For example, in addition to the discomfort of the injection and the requirement of a professional for administration, side effects may be very pronounced including, but not limited to, respiratory depression.
Opioid agonists may be associated with opioid antagonists in the case of opioid poisoning and/or to limit certain side effects. Opioid antagonists, in contrast to opioid agonists, are characterized by their inhibitory activity of at least one opioid receptor. Opioid antagonists may be divided into two main classes: specific opioid antagonists and non-specific opioid antagonists, e.g., naloxone, naltrexone, and nalmefene.
Another class of drugs used therapeutically includes benzodiazepines. Benzodiazepines are used primarily for their main properties: hypnotics, anxiolytics, anti epileptics, muscle relaxant, and amnesic.
Commonly used benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clotiazepam, clorazepate, diazepam, estazolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, temazepam, tetrazepam, triazolam, etc.
Benzodiazepines may have many undesirable side effects including amnesia, abnormal behavior, tolerance, respiratory depression, etc. Benzodiazepines may be associated with a benzodiazepine antagonist, e.g., flumazenil, in the case of benzodiazepines poisoning or to limit certain side effects, e.g., respiratory depression. Benzodiazepine antagonists, unlike benzodiazepines, are characterized by their inhibitory activity of benzodiazepines.
Despite the strong need for treating pain with analgesic active ingredients such as opioid agonists and benzodiazepines, that need is limited by undesirable side effects, particularly respiratory depression. Specifically, regarding the public health, there is a need for reduced respiratory depression, limited misuse, and other to avoid other problems associated with addictive drugs. In addition, regarding ergonomics of treatment, there is a need for secure management made easier, noninvasive administration and limited post-treatment harm. Regarding the costs of using such drugs in treatment, there also is a need for limited intervention of the hospital staff, reduced hospitalization durations, reduced misuse impacting health systems, and reduced costs of distribution networks, among others.
In particular, there is a long felt need for a technical solution for delivering active ingredients for treating pain in an independently patient-controlled manner without any medical facility, while at the same time, managing the undesirable side effects of such treatment. This need especially concerns people including, for example, soldiers, journalists, adventurers, explorers, hunters, hikers, climbers, who may be far from any medical personnel or treatment center, e.g., hospital, clinic or health center. Indeed, these people are often found in places where the objective dangers involving the maintenance of bodily integrity are quite significant, and the risk of inflicting traumatic injury is high. Therefore there is a need for a single therapeutic solution for managing various situations of which there is a manifestation of pain through proper administration of suitable active pharmaceutical ingredients, while at the same time, avoiding undesirable side effects.
Various efforts have been made to improve opioid therapy, but satisfactory results have yet to be obtained. For example, Chinese application CN 102068697 describes combining an opioid agonist and an opioid antagonist in attempt to limit the adverse effects of the opioid agonist without impacting its effect. Specifically, the application teaches a nasal spray comprising a mixture of fentanyl/naltrexone. However, the application fails to describe limiting the number of administrations or controlling the potential side effects once the opioid antagonist metabolizes.
U.S. Patent Pub. No. 2007/0186923, assigned to AcelRx Pharmaceuticals, describes a medical delivery device for the administration of opioid agonists in the oral mucosa. The device has a safety component which prevents opioid antagonist spill when attempting to recover the opioid agonist solution. The application also describes a security system that ensures neutralization of the effect of the opioid agonist composition in case of attempted hijacking, making the composition unusable. Under normal conditions, no mixing occurs between the opioid agonist and the opioid antagonist, and no antagonist administration takes place.
WO 2012024106, assigned to the University of Florida, describes a complex system consisting of the acquisition of pharmacokinetic and pharmacodynamic data, and algorithmic analysis, wherein the response may be variable. The application specifies that the oximeter is not considered a reliable device for detecting abnormality, and that other probes are preferred. In addition, the device is not transportable.
WO 1996040332, assigned to Go Medical, describes a medical device for intranasal administration of an opioid agonist. The device includes a solution comprising an opioid agonist and other active molecules other than opioid antagonists. Thus, the application does not envisage the incorporation of opioid antagonists. In addition, the application fails to describe limiting misuse, and only describes a control system wherein a patient uses “good faith.”
U.S. Pat. No. 4,464,378 to Hussain describes methods of intranasal administration of antagonists and corresponding formulations in, for example, gel form. The objective stated in that patent is to circumvent the difficulties encountered with the use of certain known products which have shown insufficient bioavailability during oral administration. That patent describes formulating solutions, gels, suspensions, and ointments containing the agonist-antagonist opioid for intranasal administration.
U.S. Pat. No. 5,629,011 to Ilium describes intranasal formulations of polar metabolites of opioid agonists in combination with an absorption promoter acting in the mucous membranes.
U.S. Pat. No. 5,767,125 to Crain describes a method of co-administration of an opioid agonist with an opioid antagonist. The opioid agonist is selected from morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalins, dynorphins, endorphins, and alkaloids and opioid peptides which behave in the same way. The opioid antagonist is selected from naltrexone, naloxone, etorphine, diprenorphine, dihydroetorphine, and alkaloids, and opioid peptides behaving in the same way. The product is administered to mice by intraperitoneal injection, but the patent raises the possibility of preparing formulations for oral, sublingual, intravenous, intramuscular, subcutaneous, and transdermal administration.
WO 2001058447 to Oshlack describes compositions containing an opioid agonist and an opioid antagonist that may be formulated for intranasal administration. In this application, the opioid antagonist is coated with a substrate, e.g., a polysaccharide, to form microspheres to control its release on the mucous membranes so as to ensure the effect of the opioid antagonist during the administration.
U.S. Pat. No. 6,948,492 to Wermeling describes systems and intranasal delivery devices regarding controlling the minimum time between intranasal self-administration of a plurality of unit doses of a pharmaceutical composition. Unit doses contained in vials are deposited on a support star around a hub that may rotate to advance the unit dosage after each use, but only after a certain predetermined time has elapsed. The support star rotates and advances the vials, the progression of which is retained by a metal spring and a shape memory alloy wire. The locking is controlled by a microprocessor which counts down between each administration. The patent does not describe co-administering an opioid agonist and an opioid antagonist, or another form of control preventing the inappropriate administration of the composition. Indeed, although it is possible for the disclosed device to self-administer subsequent doses of opioid composition, the dosage is not in a physiological condition to withstand such administration.
As described above, efforts to improve opioid therapy include the administration of opioid agonists and opioid antagonists together in a single composition. However, devices made for simultaneous administration of opioid agonists and opioid antagonists prevents the opioid agonists from being fully effective prior to the mitigating effects of the opioid antagonists. For example, U.S. Pat. No. 7,875,001 to Minotti describes a nasal spray apparatus for simultaneously introducing at least two medicaments into a patient's nasal cavity. The medicaments are mixed prior to administration and are not administered individually and sequentially. Similarly, U.S. Patent App. No. 2006/0207596 to Lane describes a dual nasal applicator system for simultaneously delivering a first and second nasal drug composition housed in separate chambers wherein the first and second nasal drug compositions remain separated until dispensed into the patient's nasal cavity. The compositions are mixed either just prior to or during administration, and are not administered individually and sequentially.
In summary, none of the efforts mentioned above resolve the problems described above. As will be discussed below, devices and methods in accordance with the principles of the present disclosure solves the aforementioned problems.